7th Annual Symposium
Physics of Cancer
October 4-6, 2016
|PoC - Physics of Cancer - Annual Symposium|
Spatial Signalling at the Membrane
Karolinska Institute, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, 171 77 Stockholm, Sweden
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Membrane proteins are key sensor components in cells and form the largest class of proteins in the druggable genome. Dyregulation in membrane protein mediated signaling is involved in allowing cells to acquire abnormal functions in cancer such as aberrant proliferation and invasion of neighboring tissues.
The significance of the biophysical context of ligands and receptors at the membrane for downstream signalling pathways is widely accepted but poorly understood due to difficulties in controlling and analysing membrane protein microenvironments at the nanoscale. DNA origami is a nanofabrication technology that uses DNA self-assembly to drive the precise formation of nanostructures. We have recently shown that DNA origami can be used to tailor the spatial distribution of protein assemblies . This new tool allows for display of well-defined protein nanoclusters in solution and is therefore amenable to the study of 3D in vitro tissue models and presents an opportunity for future translational applications. Therefore, DNA origami/ligand nanoclusters form a nanotool that is well suited to investigate the roles of the biophysical properties of ligand/receptor interactions on downstream signaling and cellular outcomes.
We have previously shown that the levels of EphA2 receptor activation depend on the spatial distribution of ephrinA5 ligands at the nanoscale . To investigate the morphological and dynamical aspects of the assembly of receptor on the cell membrane, we are using Stochastic Optical Reconstruction Microscopy (STORM). In order to identify the downstream signaling pathways modulated by receptor spatial distribution and lateral mobility, we are using RNA-sequencing and functional assays.
We developed tailor-made ligand nanoclusters that have the potential to contribute to understanding of the fundamental mechanisms of action of physical variables at the membrane in ligand/receptor signaling. This work has the potential to provide insights relevant for the development of new types of pharmacological interventions that target the biophysical context of the ligand-receptor interaction.